Throughout this application various publications are referenced by arabic numerals within parentheses. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Recently there has been increased attention focused on the binding of metal complexes to nucleic acids and nucleic acid constituents (1). This interest stems in large part from the successful application of cis-dichlorodiammineplatinum(II) (cis-DDP or cisplatin) as an antitumor drug (2). See also, U.S. Pat. Nos. 4,273,755 (1981); 4,302,446 (1981); 4,310,515 (1982); 4,339,437 (1982) and 4,451,447 (1984). More recently chiral transition metal complexes have been utilized in designing specific probes for nucleic acid structure. The tris(phenanthroline) complexes of zinc(II) (3) and ruthenium(II) (4) display enantiomeric selectivity in binding to DNA by intercalation. Because of their high specificity in intercalative binding to right- or left-handed DNAs, enantiomers of tris(4,7-diphenylphenanthroline) ruthenium(II) and cobalt(III) provide respectively spectroscopic probes (5) and cleaving agents (6) that are DNA conformation-specific. Such complexes bind to DNA only under suitable intercalating conditions, and do not bind to DNA in a covalent fashion.
It has now been discovered that certain bis-substituted metal complexes of phenanthrolines are capable of binding covalently and stereospecifically to DNAs. Such complexes are useful in stereospecific labeling and cleavage of DNAs and are further useful as antitumor agents.